title: Endothelin-1 release during the early phase of reperfusion is a mediator of myocardial reperfusion injury.
abstract: OBJECTIVE
  In acute myocardial infarction, left ventricular (LV) unloading reduces endothelin-1 (ET-1) release. We tested that endogenous ET-1 released during acute myocardial infarction might mediate ischemia/reperfusion (I/R) injury by stimulating increased intracellular calcium concentration, [Ca(2+)]i, and apoptosis.
  
  
  METHODS
  Rabbits were subjected to 1 h of coronary artery occlusion followed by 3 h of reperfusion. Unloading was initiated 15 min prior to reperfusion and was maintained during reperfusion. The control group was subjected to reperfusion. Animals were treated with ET-1 receptor antagonist BQ123. In parallel, isolated rabbit cardiomyocytes subjected to simulated I/R with or without ET-1 or BQ123, intracellular Ca(2+) and cell death were assessed with flow cytometry.
  
  
  RESULTS
  LV unloading prior to reperfusion reduced myocardial ET-1 release at 2 h of reperfusion. Infarct size was reduced in unloaded and BQ123 groups versus controls. LV unloading and BQ123 treatment reduced the percentage of apoptotic cells associated with increases in Bcl-2 protein levels in ischemic regions. BQ123 reduced both ET-1-induced [Ca(2+)]i increase and cell death for myocytes subjected to stimulated I/R.
  
  
  CONCLUSIONS
  We propose that components of reperfusion injury involve ET-1 release which stimulates calcium overload and apoptosis. Intravenous ET-1 receptor blockade prior to reperfusion may be a protective adjunct to reperfusion therapy in acute myocardial infarction patients.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tamareille
authors.forename: Matthew
authors.initials: M
authors.lastname: Terwelp
authors.forename: James
authors.initials: J
authors.lastname: Amirian
authors.forename: Patricia
authors.initials: P
authors.lastname: Felli
authors.forename: Xiu Q
authors.initials: XQ
authors.lastname: Zhang
authors.forename: William H
authors.initials: WH
authors.lastname: Barry
authors.forename: Richard W
authors.initials: RW
authors.lastname: Smalling
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D003331:Coronary Vessels; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D006439:Hemodynamics / Q000502:physiology; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011817:Rabbits; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium